In traumatic axonal injury, Ca2+ influx across a focally damaged axolemma precipitates local mitochondrial failure, degradation of the subaxolemmal spectrin network and compaction of neurofilaments, which collectively contribute to axonal failure. In previous studies, cyclosporin A pretreatment preserved mitochondrial integrity and attenuated axonal failure following trauma. Here we investigate whether this CsA-linked protection was related to the concomitant blunting of intra-axonal, Ca2+-induced cytoskeletal changes in traumatic axonal injury, assessed with antibodies targeting spectrin proteolysis and neurofilament compaction. CsA pretreatment dramatically reduced Ca2+-induced cytoskeletal damage following injury; CsA-treated rats, compared with vehicle-treated rats, displayed a 70% decrease in immunoreactive/damaged profiles. We suggest that CsA-mediated preservation of mitochondrial integrity enables the restoration of ionic and metabolic homeostasis thereby short-circuiting Ca2+-induced proteolysis in injured axons.